Areas of research
Myeloma functional heterogeneity in clinical drug resistance and residual disease
Myeloma heterogeneity is the single most important obstacle for optimal therapeutic targeting. A complex genetic landscape, epigenetic mechanisms and cues from tumour microenvironments shape the phenotypic and functional diversification of myeloma cells, which underpins drug resistance and later relapsed disease. Differential transcriptional profiles and gene expression regulatory mechanisms at diagnosis and residual disease provide insight into the biology of drug resistance and reveal novel disease vulnerabilities.
The lab is particularly interested in the biology of BCL2 family proteins. BCL2 inhibition is a promising targeted therapy for t(11;14) myeloma and a unique paradigm of treatment directed by genetics.
Myeloma kidney disease and MGRS
Myeloma kidney disease is a debilitating complication with a profound impact on treatment outcome and survival. Monoclonal Gammopathy of Renal Significance (MGRS) is a rare disease, where small amounts of highly nephrotoxic immunoglobulins or free light chains, produced by otherwise subclinical plasma cell clones, resulting in a bewildering array of renal histopathology and kidney disease.
The lab collaborates with Renal Medicine and Histopathology at Imperial to establish experimental vitro and vivo models of myeloma cast nephropathy and MGRS. We study the proinflammatory and profibrotic pathways induced by the nephrotoxic immunoglobulins and develop novel diagnostics and therapeutic strategies.
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Journal articleKousios A, Duncan N, Charif R, et al., 2019,
Autologous stem cell transplant for the treatment of type I crystal cryoglobulinaemic glomerulonephritis caused by monoclonal gammopathy of renal significance (MGRS), Kidney International Reports, Vol: 4, Pages: 1342-1348, ISSN: 2468-0249
Cryoglobulins (CGs) are immunoglobulins that precipitate at temperatures below 37°C and dissolve again after rewarming. Cryoglobulinemia may be asymptomatic or cause end-organ damage by CG precipitation in small- to medium-sized blood vessels.1 In their seminal work, Brouet et al.2 classify cryoglobulinemias into 3 subgroups according to CG composition and clonality. In type II cryoglobulinemia there is a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG. In type III, CGs consist of polyclonal IgM and IgG.1 Type II and III cryoglobulinemias are also referred to as mixed cryoglobulinemias and are often caused by chronic hepatitis C infection and less frequently by autoimmune diseases or other viral infections (hepatitis B infection, HIV).3CGs in type I cryoglobulinemia are monoclonal Igs (MIg), also known as paraproteins, commonly IgG, IgM subtypes, or free light chains. The underlying pathological process is a plasma cell or B-cell lymphoproliferative disease, such as multiple myeloma (MM), Waldenström macroglobulinemia, chronic lymphocytic leukemia, or other B-cell non-Hodgkin lymphoma. However, in approximately 40% of symptomatic cases, the plasma cell or B-cell clone is too small to fulfill the diagnostic criteria of MM or overt lymphoma. The term monoclonal gammopathy of undetermined significance (MGUS) used for these cases is a misnomer, as the MIg causes disease regardless of the size and tumor burden.4 For cases with renal involvement, the International Kidney and Monoclonal Gammopathy Research Group introduced the term monoclonal gammopathies of renal significance (MGRS).5 The updated MGRS definition includes monoclonal gammopathies that cause renal disease but have low tumor burden and thus treatment from the hematological standpoint is not imminently indicated.6 These patients may have fewer than 10% plasma cells in bone marrow biopsy, smoldering myeloma, or low-grade lymphomas.7 MGRSs are not of undetermined significanc
Journal articleKousios A, Storey R, Troy-Barnes E, et al., 2019,
Plasmacytoma-like post-transplant lymphoproliferative disease in a disused arterio-venous fistula: the importance of histopathology., Kidney International Reports, Vol: 4, Pages: 749-755, ISSN: 2468-0249
Common causes of swelling in arteriovenous fistulae (AVFs) include thrombosis, infection, aneurysm, and superior vena cava (SVC) obstruction secondary to previous dialysis vascular catheter use. Malignancies confined in AVFs are rare and have been described in case series and case reports, mostly in immunosuppressed patients.1 Patients who undergo transplantation frequently have functioning or nonfunctioning AVFs. The risk of malignancy is increased in this patient group and thus should be considered in patients presenting with symptomatic AVF. The most common histopathological diagnosis is angiosarcoma.1, 2 Plasmacytoma-like posttransplant lymphoproliferative disease (PTLD) confined in an AVF has not been previously described.
Journal articleLeung N, Bridoux F, Batuman V, et al., 2019,
Journal articlePavlu J, Auner H, Szydlo RM, et al., 2017,
Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation., Bone Marrow Transplantation, Vol: 52, Pages: 1599-1601, ISSN: 1476-5365
Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient’s weight. One fraction was used for the first transplant after median storage of 60 days (range, 17–165) and another fraction was used after median storage of 1448 days (range, 849–3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11–21) after the first and 13 days (10–20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.
Conference paperBeckerson J, Szydlo RM, Hickson M, et al., 2016,
Impact of Nutrition on Non-Relapse Mortality and Acute Graft Versus Host Disease during Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies, 59th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH)/Symposium on the Basic Science of Hemostasis and Thrombosis, Publisher: American Society of Hematology, Pages: 2226-2226, ISSN: 0006-4971
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